Bivalirudin Monotherapy Improves 30-day Clinical Outcomes in Diabetics with Acute Coronary Syndrome: Report from the ACUITY Trial Frederick Feit, Steven Manoukian, Ramin Ebrahimi, Charles Pollack, Magnus Ohman, Michael Attubato, Roxana Mehran and Gregg Stone

Bivalirudin Monotherapy Improves 30-day Clinical Outcomes in Diabetics with Acute Coronary Syndrome: Report from the ACUITY Trial Shareholder: Johnson and Johnson, Medicines Co., Millenium Pharmaceuticals; Consultant: Medicines Co. Conflicts:

ACS in Diabetics: Metabolic Abnormalities  Increased blood glucose causes coronary artery inflammation and is prothrombotic  Increased generation of thrombin, CRP, fibrinogen, von Willebrand factor, factors VII and VIII, and platelet factor 4  Increased expression of platelet activation markers including p-selectin, which mediates platelet-leukocyte interactions  Higher proportion of platelets expressing GPIIb/IIIa receptors

ACS in Diabetics: Background  Based on prior data including a meta- analysis of ACS trials current clinical guidelines recommend the use of GPIIb/IIIa inhibitors (GPI) in diabetic patients with ACS, especially those in whom PCI is planned 1  In the ACUITY Trial 13,819 pts, including 3852 diabetics, with moderate or high risk ACS, undergoing an early invasive strategy were randomly assigned to either the standard of care: Heparin (UFH or enoxaparin) + GPI; or, Bivalirudin + GPI; or Bivalirudin with provisional GPI 1. Roffi et al. Circulation. 2001;104:

ACS in Diabetics: Methods  We compared adverse events: composite ischemia (death, nonfatal MI, unplanned ischemia driven revascularization), major bleeding and net clinical outcome (composite ischemia or bleeding) within the first 30 days in diabetic vs. nondiabetic pts  We compared the same 30-day end points in diabetic pts by treatment group

ACUITY Design ACS: Unstable angina or NSTEMI, N=13,819 Chest pain >10’ within 24 hours, plus Biomarker +, or Dynamic ECG changes, or Documented CAD or all other TIMI risk criteria Bivalirudin + IIb/IIIa inhibitor Enoxaparin or UFH + IIb/IIIa inhibitor Bivalirudin + provisional IIb/IIIa ASA Clopidogrel per local practice Cath within 72 hours PCI, CABG or medical management 30 day endpoints Death, MI, IUR, ACUITY major bleeding (net clinical outcome) Prior UFH, LMWH (1 dose), eptifibatide and tirofiban allowed Stone et al. Presented 2006; ACC

UF HeparinEnoxaparinBivalirudin U/Kgmg/Kgmg/kg Bolus601.0 sc bid0.1 iv Infusion/h iv PCI ACT s 0.30 iv bolus iv bolus bolus iv 1.75/h infusion iv 4 CABGPer institution Per institution 5 Medical mgtNone 6 Study Medications  Anti-thrombin agents (started pre angiography) 1 Target aPTT seconds 2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if IIb/IIIa inhibitor not used 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

ACS in Diabetics: Angiographic Triage Diabetes (N=3852) % No Diabetes (N=9857) % # pts with angiography Triaged procedure results PCI CABG * Medical management * - p<0.001

ACS in Diabetics: Baseline Characteristics Diabetes (N=3852) No Diabetes (N=9857) P-value Age mean, (median, [range], yrs) 63.8 (64.0, [25-92])62.1 (62.0, [20-95])<0.001 Age ≥ 65 yrs49%43.4%<0.001 Age ≥ 75 yrs17.9%17.6%0.65 Female34.9%28.2%<0.001 Weight mean, (median, [IQR], kg) 90.8 (88.5, [77-102])83.3 (82.0, [72-94])<0.001 Diabetes – insulin requiring 31.0%- Hypertension83.6%60.5%<0.001 Hyperlipidemia68.8%51.3%<0.001 Current smoker21.4%32.0%<0.001 Prior MI36.2%29.4%<0.001 Prior PCI46.1%36.1%<0.001 Prior CABG23.7%15.7%<0.001 Creatinine Clearance*19.8%18.8% * CrCL <60 mL/min

ACS in Diabetics: Baseline High Risk Features Diabetes % No Diabetes % p-value  Baseline cardiac biomarker  <0.001  - Troponin  53.4%60.0%<0.001 ST-segment  ≥1mm 33.0%35.7%0.003  Baseline cardiac biomarker  or ST-segment  <0.001

Diabetes vs. No Diabetes P = P = P = † Heparin=unfractionated or enoxaparin ACS in Diabetics: 30-Day Outcomes

Diabetes % No Diabetes % P-value Net clinical outcome Composite ischemia Death/MI Death MI Q-wave MI Non Q-wave MI Unplanned revasc Bleeding (non CABG)

Diabetic ACS Patients Baseline Characteristics by Treatment Heparin † + GP IIb/IIIa (N=1298) Bivalirudin + GP IIb/IIIa (N=1267) Bivalirudin alone (N=1287) Age mean (median [range], yrs) 64.0 (65, [25-87])63.9 (64, [26-90])63.5 (64, [32-92]) Age ≥75 yrs, % Female, % Weight mean (median [IQR]) kg 90.7 (88 [77-102])89.7 (87 [77-100])91.9 (90 [78-103]) Caucasian, % Diabetes–Insulin req, % Hypertension, % Hyperlipidemia, % Current smoker, % Prior MI, % Prior PCI, % Prior CABG, % Prior CVA, % Creatinine Clearance*, % * creatinine clearance <60 mL/min † Heparin = unfractionated or enoxaparin

Diabetic ACS Patients: Baseline High Risk Features by Treatment Group Heparin † + GP IIb/IIIa % (n=1298) Bivalirudin + GP IIb/IIIa % (n=1267 Bivalirudin alone % (n=1287)  Baseline cardiac biomarker   - Troponin  ST-segment  ≥1mm 33.7%33.6%31.7%  Baseline cardiac biomarker  or ST-segments  * p<0.05 for comparison with H + GP IIb/IIIa † Heparin = unfractionated or enoxaparin

Diabetic ACS Patients: 30-Day Endpoints by Treatment Group Heparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa *Heparin = unfractionated or enoxaparin P = 0.43 P = 0.64P = 0.94

Diabetic ACS Patients: 30-Day Endpoints Heparin* + GP IIb/IIIa vs. Bivalirudin alone *Heparin = unfractionated or enoxaparin P = 0.02 P = 0.39P=0.0002

17 Diabetic ACS Patients: Components of Ischemic Endpoint Heparin* + IIb/IIIa vs. Bivalirudin Alone P = 0.39P = 0.32P= 0.27P = 0.37 *Heparin=unfractionated or enoxaparin

30 day events (%) Diabetic ACS Patients: Myocardial Infarction Classification* 5.6% 4.7% Heparin † + IIb/IIIa vs. Bivalirudin Alone *CEC-adjudicated † Heparin=unfractionated or enoxaparin Heparin + IIb/IIIa Q-wave 1.6% (N=1298) Bivalirudin alone (N=1287) Non Q-wave 3.9% Q-wave 0.8% Non Q-wave 4.0% p = 0.27 p = 0.05 p = 0.87

Diabetic ACS Patients: Bleeding Endpoints 30-days Heparin † +GP IIb/IIIa ( N=1298) Bivalirudin alone (N=1287) p- value ACUITY Scale - Major Bleed, all14.3%11.0% Major, non-CABG7.1%3.7% Minor, non-CABG21.1%12.3%<0.001 TIMI Scale, non-CABG - Any7.5%3.7%< Major2.4%0.9% Minor7.0%3.6%<0.001 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor † Heparin=unfractionated or enoxaparin

Insulin-dependent Diabetic ACS Patients: 30-Day Endpoints by Treatment Group Heparin † + GP IIb/IIIa vs. Bivalirudin alone P = 0.23 P = 0.74P = 0.04 † Heparin=unfractionated or enoxaparin

Diabetic Patients with ACS : Conclusions  Compared with non-diabetics, diabetic patients have worse net clinical outcomes at 30 days (12.8% vs. 10.5%; p=0.0002), resulting from significantly higher rates of the composite ischemic end point (8.6% vs. 7.2%; p=0.0037) and non-CABG major bleeding (5.7% vs. 4.2%; p=0.0002)  In diabetic patients, compared with the standard of care, heparin (UFH or enoxaparin) + GPIIb/IIIa, bivalirudin + GPIIb/IIIa was not better for protection from ischemic events or bleeding and resulted in similar net clinical outcome

Diabetic Patients with ACS: Conclusions  Compared to those receiving the reference standard, diabetics receiving bivalirudin monotherapy, with provisional GPIIb/IIIa in 7.9%, had similar protection from ischemic events (7.8% vs. 8.8%; p=0.39) and a marked reduction in major bleeding (3.7% vs. 7.1%; p=0.0002) with improved net clinical outcome (10.8% vs. 13.7%; p=0.02)  These 30-day outcomes suggest that bivalirudin monotherapy is safe and effective for diabetic patients with ACS, including those requiring insulin  One-year clinical and economic data will determine whether this regimen will become the standard of care for these patients.